We propose five core aims evaluating novel strategies to reduce healthcare associated infections. These aims include two T0, two T1, and one T2 translational research topic areas. We chose these topics because 1) they have high potential to lead to improvements in health outcomes, 2) they take advantage of our prior work in these domains, and 3) they will strengthen our infrastructure and improve our ability to respond to new topics CDC may ask the Epicenters to address. Two topics address prevention of serious MRSA infection: 1) We will identify virulence genes in MRSA by comparing the genes in pathogenic MRSA isolates to those in non- pathogenic isolates. Our ability to work with full sequence data from 300 pedigreed isolates provides a unique opportunity to identify targets for novel therapeutics. This T0 work builds on an existing collaboration with geneticists at the MIT/ Harvard Broad Institute and uses an existing specimen bank. 2) We will assess the potential utility of retapamulin for topical decolonization when mupirocin resistance makes the latter agent unusable. At present, there is no approved second line topical agent for MRSA decolonization. This T1 work will take advantage of a funded RCT studying long term decolonization. Two topics deal with complications of ventilator care: 3) We will explore the potential utility of chlorhexidine for gastric decontamination to reduce the incidence of ventilator-associated pneumonia and other nosocomial infections without selecting antimicrobial resistance. A successful T1 study will help position chlorhexidine for a fuller evaluation. 4) We will evaluate the relationship of different sedating agents, especially dexmedetomidine, with risk of ventilator associated pneumonia. This T0 study will build the evidence base for sedation management as a strategy to prevent hospital acquired infections and use the unique electronic data resources from our collaboration with Hospital Corporation of America (HCA), a 160+ hospital organization, to inform the need for a formal clinical trial. Our last study 5) will test the impact of real-time cluster detection on the size, duration, and number of nosocomial outbreaks in hospitals. This T2 study will cover all nosocomial pathogens, including Gram positive and Gram negative bacteria, and all major types of nosocomial infections, including bloodstream, surgical site, urinary tract, and others. We further describe how our extensive local, regional, and national collaborations contribute to a ready infrastructure to respond to future healthcare epidemiology needs and projects as they arise. Our comprehensive networks encompass three state health departments, numerous adult and pediatric facilities across the US, regional population laboratories including inpatient, nursing home, and outpatient facilities, as well as a large multi-center microbiology laboratory and health informatics system. These collaborative alliances are the culmination of productive research partnerships over many years and provide a robust response system for healthcare associated infection prevention research.